The advantages of cochleates are numerous. For example, cochleates are more stable than aqueous structures such as liposomes, they can be stored lyophilized which provides the potential to be stored for long periods of time at room temperatures, they maintain their structure even after lyophilization (whereas liposome structures are destroyed by lyophilization), and they are non-toxic.
Cochleate structures have been prepared first by D. Papahadjopoulos as an intermediate in the preparation of large unilamellar vesicles. U.S. Pat. No. 4,078,052. Methods of making and using cochleates to deliver a variety of molecules have been disclosed, e.g., in U.S. Pat. Nos. 5,994,318 and 6,153,217.
In these methods, prior to precipitation of the cochleates, the material to be encochleated is introduced into liposomes by solubilization of the lipid and material in solvent, removal of the solvent to form a dry lipid film, then by hydration of the lipid and components to be encochleated. Alternatively, material and lipid may be solublized in detergent which may be removed by dialysis or other methods. These steps are time consuming, represent added expense in manufacturing and product costs, and can in some instances affect the activity and/or stability of the encochleated material.
Additionally, cochleates are highly susceptible to aggregation, and thus particle size and particle size distribution can be highly variable and unstable after preparation and removal from the two-phase polymer system. The ability of drugs to be administered via the oral route depends on several factors. The drug typically must be sufficiently soluble in the gastrointestinal fluids in order for the drug to be transported across biological membranes for an active transport mechanism or have a sufficiently small particle size, such that it can be absorbed through the Peyer's Patches in the small intestine and through the lymphatic system. Particle size is an important parameter when oral delivery is to be achieved (see Couvreur P. et al, Adv. Drug Delivery Reviews 10:141-162, 1993). Thus, it would be advantageous to be able to control and stabilize the particle size and particle size distribution of encochleated materials.
There also exists a need for delivery vehicles that can safely and effectively deliver cargo moieties that are poorly absorbed by the body (e.g., weakly basic drugs). For example, aminoglycopeptides (e.g., vancomycin), are poorly absorbed through the GI tract and are difficult to deliver to cells harboring bacteria. Accordingly, in order to administer an effective amount of drug against a bacterial infection, large amounts of drug are ingested to not only account for poor absorption through the GI tract, but also poor delivery to the site of infection. Consequently, a toxic level of drug can accumulate in the GI tract (e.g., in the kidneys) or the blood stream and can lead to serious illness, such as erythematous or urticarial reactions, flushing, tachycardia, and hypotension. Aminoglycosides (e.g., streptomycin and tobramycin) are similarly problematic because of the risk of nephrotoxicity and ototoxicity due to poor absorption, which can lead to acute, renal, vestibular and auditory toxicity. While these drugs can be delivered intravenously to bypass the issue of poor GI tract absorption, uptake by the cells is still problematic. That is, even at high concentrations, aminoglycopeptides and aminoglycosides can not penetrate the cell membrane in order to contact the bacteria. Additionally, echinocandins (e.g., caspofungin), a new, less toxic class of antifungal drugs, still have unwanted side effects and poor oral bioavailability. As such, they are generally administered intravenously.
The present invention addresses each of these drawbacks.